This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. DNA breaks are critical for many cellular and developmental processes, but must be correctly repaired to prevent genome instability. The objectives of this project are to understand the roles of DNA double strand break repair (DSBR) in normal hematopoietic development, and to determine whether DSBR defects in specific cell types in the bone marrow may relate to cancer development. DSBR is known to be a key factor in lymphoid tumor suppression, but has been less well characterized in other cell types. I hypothesize that DSBR is critical in both hematopoietic cells and their surrounding microenvironments to promote normal development and prevent neoplastic transformation. Using mice deficient for DSBR, with or without the tumor suppressor p53, we will test this hypothesis by measuring the fitness and function of normal hematopoietic stem, progenitor, and progeny cells;and by evaluating tumorigenicity in DSBR competent or defective bone marrow and lymphoid microenvironments. Aim 1. To evaluate the extent to which NHEJ is required for normal function or homeostasis of cells in the hematopoietic compartment, we will: (1) test whether DSBR-deficient HSCs or their descendants are impaired for differentiation or function and (2) measure genome instability in DSBR-deficient stem and progenitor cell populations Aim 2. To determine whether specific stem cell or lymphoid microenvironments participate in shaping the lymphoma phenotype, we will: (1) determine whether tumorigenesis is differentially influenced by lympho-competent versus lympho-deficient bone marrow microenvironments;and (2) test whether tumor cells become adapted to specific secondary lymphoid microenvironments